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Adenosine A2A Receptor

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Catherine Ledent – One of the best experts on this subject based on the ideXlab platform.

  • uncovering caffeine s Adenosine A2A Receptor inverse agonism in experimental parkinsonism
    ACS Chemical Biology, 2014
    Co-Authors: Victor Fernandezduenas, Kenneth A. Jacobson, Jaume Taura, Catherine Ledent, Masahiko Watanabe, Jean-pierre Vilardaga, Maricel Gomezsoler, Marc Lopezcano, Francisco Ciruela

    Abstract:

    Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an Adenosine A2A Receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the Receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.

  • Uncovering Caffeine’s Adenosine A2A Receptor Inverse Agonism in Experimental Parkinsonism
    ACS chemical biology, 2014
    Co-Authors: Víctor Fernández-dueñas, Kenneth A. Jacobson, Maricel Gómez-soler, Marc López-cano, Jaume Taura, Catherine Ledent, Masahiko Watanabe, Jean-pierre Vilardaga, Francisco Ciruela

    Abstract:

    Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an Adenosine A2A Receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the Receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.

  • Reduced response to the formalin test and lowered spinal NMDA glutamate Receptor binding in Adenosine A2A Receptor knockout mice.
    Pain, 2006
    Co-Authors: Martin Hussey, Catherine Ledent, Geoffrey D. Clarke, Susanna M.o. Hourani, Ian Kitchen

    Abstract:

    Adenosine is a neuromodulator with complex effects on pain pathways. Mice lacking the Adenosine A2A Receptor are hypoalgesic, and have altered analgesic responses to Receptor-selective opioid agonists. These and other findings suggest a role for the Adenosine A2A Receptor in sensitizing afferent fibres projecting to the spinal cord. To test this hypothesis formalin (20 microl, 5%) was injected into the paw and nociceptive responses were measured in wildtype and Adenosine A2A Receptor knockout mice. There was a significant reduction in nociception associated with sensory nerve activation in the knockout mice as measured by time spent biting/licking the formalin-injected paw and number of flinches seen during the first phase, but only the number of flinches was reduced during the second inflammatory phase. In addition, the selective Adenosine A2A antagonist SCH58261 (3 and 10 mg/kg) also antagonised both phases of the formalin test. We also labelled NMDA glutamate and NK1 Receptors in spinal cord sections as an indirect measure of nociceptive transmission from peripheral sites to the spinal cord. [3H]-Substance P binding to NK1 Receptors was unaltered but there was a substantial reduction in binding of [3H]-MK801 to NMDA glutamate Receptors in all regions of the spinal cord from knockout mice. The decrease in NMDA glutamate Receptor binding may reflect reduced peripheral sensory input to the spinal cord during development and could relate to the hypoalgesia in this genotype. These results support a key role for the Adenosine A2A Receptor in peripheral nociceptive pathways.

Irving L Kron – One of the best experts on this subject based on the ideXlab platform.

  • ex vivo lung perfusion with Adenosine A2A Receptor agonist allows prolonged cold preservation of lungs donated after cardiac death
    The Journal of Thoracic and Cardiovascular Surgery, 2016
    Co-Authors: Cynthia E Wagner, Nicolas H Pope, Eric J Charles, Mary E Huerter, Ashish Sharma, Morgan Salmon, Benjamin T Carter, Mark H Stoler, Victor E Laubach, Irving L Kron

    Abstract:

    Abstract Objective Ex vivo lung perfusion has been successful in the assessment of marginal donor lungs, including donation after cardiac death (DCD) donor lungs. Ex vivo lung perfusion also represents a unique platform for targeted drug delivery. We sought to determine whether ischemia-reperfusion injury would be decreased after transplantation of DCD donor lungs subjected to prolonged cold preservation and treated with an Adenosine A2A Receptor agonist during ex vivo lung perfusion. Methods Porcine DCD donor lungs were preserved at 4°C for 12 hours and underwent ex vivo lung perfusion for 4 hours. Left lungs were then transplanted and reperfused for 4 hours. Three groups (n = 4/group) were randomized according to treatment with the Adenosine A2A Receptor agonist ATL-1223 or the dimethyl sulfoxide vehicle: Infusion of dimethyl sulfoxide during ex vivo lung perfusion and reperfusion (DMSO), infusion of ATL-1223 during ex vivo lung perfusion and dimethyl sulfoxide during reperfusion (ATL-E), and infusion of ATL-1223 during ex vivo lung perfusion and reperfusion (ATL-E/R). Final Pao 2 /Fio 2 ratios (arterial oxygen partial pressure/fraction of inspired oxygen) were determined from samples obtained from the left superior and inferior pulmonary veins. Results Final Pao 2 /Fio 2 ratios in the ATL-E/R group (430.1 ± 26.4 mm Hg) were similar to final Pao 2 /Fio 2 ratios in the ATL-E group (413.6 ± 18.8 mm Hg), but both treated groups had significantly higher final Pao 2 /Fio 2 ratios compared with the dimethyl sulfoxide group (84.8 ± 17.7 mm Hg). Low oxygenation gradients during ex vivo lung perfusion did not preclude superior oxygenation capacity during reperfusion. Conclusions After prolonged cold preservation, treatment of DCD donor lungs with an Adenosine A2A Receptor agonist during ex vivo lung perfusion enabled Pao 2 /Fio 2 ratios greater than 400 mm Hg after transplantation in a preclinical porcine model. Pulmonary function during ex vivo lung perfusion was not predictive of outcomes after transplantation.

  • transplantation lungex vivo lung perfusion with Adenosine A2A Receptor agonist allows prolonged cold preservation of lungs donated after cardiac death
    The Journal of Thoracic and Cardiovascular Surgery, 2016
    Co-Authors: Cynthia E Wagner, Nicolas H Pope, Eric J Charles, Mary E Huerter, Ashish Sharma, Morgan Salmon, Benjamin T Carter, Mark H Stoler, Victor E Laubach, Irving L Kron

    Abstract:

    Objective
    Ex vivo lung perfusion has been successful in the assessment of marginal donor lungs, including donation after cardiac death (DCD) donor lungs. Ex vivo lung perfusion also represents a unique platform for targeted drug delivery. We sought to determine whether ischemia-reperfusion injury would be decreased after transplantation of DCD donor lungs subjected to prolonged cold preservation and treated with an Adenosine A2A Receptor agonist during ex vivo lung perfusion.

Francisco Ciruela – One of the best experts on this subject based on the ideXlab platform.

  • uncovering caffeine s Adenosine A2A Receptor inverse agonism in experimental parkinsonism
    ACS Chemical Biology, 2014
    Co-Authors: Victor Fernandezduenas, Kenneth A. Jacobson, Jaume Taura, Catherine Ledent, Masahiko Watanabe, Jean-pierre Vilardaga, Maricel Gomezsoler, Marc Lopezcano, Francisco Ciruela

    Abstract:

    Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an Adenosine A2A Receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the Receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.

  • Uncovering Caffeine’s Adenosine A2A Receptor Inverse Agonism in Experimental Parkinsonism
    ACS chemical biology, 2014
    Co-Authors: Víctor Fernández-dueñas, Kenneth A. Jacobson, Maricel Gómez-soler, Marc López-cano, Jaume Taura, Catherine Ledent, Masahiko Watanabe, Jean-pierre Vilardaga, Francisco Ciruela

    Abstract:

    Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an Adenosine A2A Receptor (A2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A2AR inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A2AR agonist, of the Receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design.